FR2513996A1 - PYRAZOLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC APPLICATION - Google Patents

Abstract

THE INVENTION CONCERNS ARYL-3 ALCOXY-5 PYRAZOLES, REPRESENTED BY GENERAL FORMULA (I): (CF DRAWING IN BOPI) IN WHICH AR REPRESENTS AN ARYL GROUP, SUBSTITUTES IF NECESSARY; R REPRESENTS A HYDROGEN ATOM OR AN ALKYL, PHENYL OR BENZYL GROUP; R AND R, IDENTICAL OR DIFFERENT, REPRESENT A HYDROGEN ATOM OR AN ALKYL GROUP, OR TOGETHER FORM A 5 TO 7-CHAIN HETEROCYCLE WITH THE NITROGEN ATOM TO WHICH THEY ARE ATTACHED; N IS AN INTEGER OF 1 TO 4; AS WELL AS THEIR SALTS OF ACIDS. APPLICATION IN THERAPEUTICS, ESPECIALLY FOR THE TREATMENT OF ARRHYTHMIA OF THE HEART.

Description

The present invention, carried out in the CERES Center laboratories

  European Society for Scientific Research is concerned with new pyrazole derivatives, a process for their preparation and their application in therapeutics. The pyrazole derivatives according to the invention are aryl-3-alkoxy-5-pyrazoles represented by the general formula (I): ## STR5 ## wherein Ar represents an aryl group, substituted on the where appropriate, R represents a hydrogen atom or an alkyl, phenyl or benzyl group; R 1 and R 2, which may be identical or different, represent a hydrogen atom or an alkyl group, or together form a 5- to 7-membered heterocyclic ring;

  with the nitrogen atom to which they are attached; N is an integer from 1 to 4.

  The subject of the invention is also a process making it possible to prepare the derivatives of general formula (I) from readily known products.

accessible, with a good return.

  The subject of the invention is also the application of the pyrazole derivatives of general formula (I) and their pharmaceutically acceptable salts, in human or veterinary therapy, in particular for the treatment of

cardiac arrhythmias.

  The aryl group represented by Ar in the general formula (I) may in particular be a phenyl group which may be substituted by one or more halogen atoms or alkyl, aleoxy, cyano, nitro or hydroxy groups R may represent a hydrogen atom or a linear alkyl group or

  branched, such as methyl, ethyl, isopropyl, n-butyl, t-butyl, iso-

  amyl, etc., or phenyl or benzyl.

  when R 1 and R 2 form a heterocycle with the nitrogen atom to which they are attached, this heterocycle may be a group supplemented by carbon atoms, and for example a pyrrolyl, pyrrolidinyl, piperidyl, azepinyl, etc .; this heterocycle may also contain one or more other heteroatoms such as nitrogen and oxygen, and there may be mentioned, for example, oxazolidinyl, pyrazolyl, piperazinyl, imidazolyl, morpholinyl, pyrazolinyl and the like. In the general formula (I) above, Ar preferably represents a phenyl group, or a phenyl group substituted with one or more halogen atoms such as chlorine, bromine or fluorine, and for example a group p- chlorophenyl or a 3,4-dichlorophenyl group R preferably represents a hydrogen atom, a lower alkyl group of 1 to 4 carbon atoms, such as a methyl, ethyl or propyl group, or a

  benzyl group R 1 and R 2 are preferably lower alkyl groups.

  1 to 4 carbon atoms, such as a methyl or isopropyl group, R 1 may be a hydrogen atom while R 2 is an alkyl group, and vice versa, or together form a heterocyclic group and more particularly a pyrrolidinyl group; , piperidyl, oxazolidinyl,

  piperazinyl, or morpholinyl N preferably takes the values 2 or 3.

  The 3-aryl-5-alkoxy pyrazoles according to the present invention exist in several forms represented by the formula (I) above and the formulas (IA) and (IB) below: Ar 0- (CH 2) Ar - ( CH) -N 0 n <NI

R 2 N N

N N -N

H

(IA) (IB) -

  Forms (I) and (IA) are predominant, but external factors can shift equilibria to form (IB). The invention is of course concerned with aryl-3-alkoxy-5-pyrazoles in all forms (I),

  (IA) and (IB) shown above.

  The invention also relates to the salts of pyrazole derivatives,

  represented by the general formula (I) above, and more particularly

  pharmaceutically acceptable salts, obtained by acting on the derivative a common mineral or organic acid such as hydrochloric acid, sulfuric, lactic, oxalic, citric, phosphoric, stearic, maleic, tartaric, etc. The reaction is carried out according to the techniques the acid and the derivative generally react in

  substantially stoichiometric proportions.

  The pyrazole derivatives according to the invention represented by the general formula (I) can be prepared from the pyrazolones of formula (II): ## STR5 ## in which Ar and R have the same meaning as in formula (I), by alkylation reaction in a basic medium with a haloalkylamine of general formula (III) X- (CH 2) n -NR 1 R 2 (III) in which X represents a halogen atom such as chlorine or bromine, and n, R 1 and R 2 retain the definitions given in the formula

General (I).

  The aryl-3-pyrazolones of formula (II) used as starting products are known compounds which can be prepared according to the usual techniques, as described for example in "The Chemistry of Heterocyclic Compounds" Weissberger Ed (1964), Intersciences Publ. The alkylation reaction of the 3-aryl pyrazolones of formula (II) with the haloalkylamines of formula (III) is carried out in a basic medium in the presence of a base such as a hydride, an amide, a carbonate or a

  alkali metal alcoholate or an amine, in an appropriate organic solvent

  prayed. The reaction may be carried out for example in the presence of sodium hydride, sodium amide, potassium hydride, sodium ethoxide, potassium carbonate, sodium carbonate, diethylamine or triethylamine. and in a solvent selected from dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran, an alcohol such as methanol or ethanol, acetone. When the solvent is an alcohol, it may be advantageous to use as alkali corresponding, and

  for example sodium ethoxide in ethanol in accordance with the

  sodium hydride is preferably used in dimethyl-

  formamide, potassium carbonate in dioxane or ethylate

sodium in ethanol.

  The reaction can be carried out at ambient temperature, but it may be preferable to heat the reaction mixture to a temperature between 30 and 100 ° C., and preferably between 40 and 70 ° C., to accelerate the reaction.

  According to a preferred embodiment of the process of the invention,

  the pyrazolone of formula (II) is dissolved in an organic solvent under a nitrogen atmosphere, a base such as sodium hydride is added,

  potassium carbonate or sodium amide, then lightly

  and the haloalkylamine of formula (III) is gradually added.

  The solvent is removed by evaporation under reduced pressure and purified

  the product obtained, by the usual techniques of acid

-basics or chromatography.

  The haloalkylamines of formula (III) used as reagents for effecting the alkylation of the pyrazolones of formula (II) according to the process of the invention are generally commercially available in the form of their hydrochlorides. It may be advantageous to convert these hydrochlorides into bases. at the time of use, dissolving them in a saturated solution of potassium carbonate and carrying out an extraction, according to the technique described in Fieser & Fieser, "Reagents for Organic Synthesis" No. IV, John Wiley & Sons (1974). )

  Examples of haloalkylamines usable according to the invention are

  more particularly, N- (2-chloroethyl) dimethyl-

2 to 43996

  amine, N- (3-chloro-propyl) -dimethylamine, or N- (2-chloroethyl) di-

  isopropylamine, or heterocyclic haloalkylamines such as N- (2-chloroethyl) -pyrrolidine, N- (2-chloroethyl) -piperidine, N- (3-chloro-propyl) -morpholine, N- (chloro) 3-propyl) -piperidine, etc. According to a variant according to the present invention, the pyrazole derivatives of general formula (I) can be prepared from an aroylacetate of ethyl of general formula (IV): Ar-C-CHR-C-OC H (IV )

II II 2 J

0 O

  o Ar and R have the same meaning as in formula (I), which is

  transforms by transesterification by means of an aminoalcohol of

  mule (V): wherein R 1 and R 2 have the same meaning as in formula (I), to obtain the compound of formula (VI): C-CHR-CO- (CH 2) nN R 1 R 2 (VI)

0 O

  on which a cyclization is carried out by means of hydrazine in a medium

  acid, providing the derivative of general formula (I).

  Transesterification to transform ethyl aroylacetate

  of formula (IV) of ketonic ester of formula (VI) is preferably carried out

  by heating in a solvent allowing azeotropic distillation

  pike; in addition, it is advantageous to operate in the presence of an acid catalyst. The solvent may be, for example, a hydrocarbon such as toluene.

or xylene.

  The cyclization reaction with hydrazine in an acidic medium, for example in a concentrated hydrochloric acid or sulfuric acid medium, may be carried out

  following a technique similar to that of HJ Backer and W Meier "Rec.

Trav Chim P B "45, 428 (1926).

'13996

  The following examples illustrate the invention without limiting its scope.

EXAMPLE 1

  p-Chlorophen-3-dimethylaminopropoxy-5-pyrazole.

  In a 500 ml flask equipped with an agitator, thermometer, refrigerator,

  managing, a dropping funnel and a nitrogen inlet, 9.5 g of p-chlorophenyl-3-pyrazolone in 70 ml of dioxane are placed under reflux, under a nitrogen atmosphere, and 4 After heating for 1 h under reflux, 7.2 g of 1-dimethylamino-3-chloropropane are added while maintaining the reaction medium under reflux; the addition is carried out gradually over 45 minutes. The mixture is kept at reflux for approximately 4 hours and then acid-base extractions are carried out according to the usual techniques.

  after removal of the solvent by evaporation under vacuum.

  After recrystallization from hexane and then from isopropyl ether,

  6.6 g of p-chlorophenyl-3-dimethylaminopropoxy-5-pyrazole (yielding

  47%) Melting point: F = 114 C (isopropyl ether) IR spectrum (Nujol) v = 3130, 3100, 1510, 1490 cm -1 NMR spectrum (CDCl 3) δ = 1.7-2.7 ( 4H), 2.2 (s, 6H), 4.0 (t, 2H), 5.8 (s, 1H), 7.3 (q, 4H), 11.2 (s, 1 H) ppm

  By the action of maleic acid in ethanol, according to the usu-

  they are prepared the maleate of the above compound.

Melting point: F = 155 ° C

EXAMPLE 2

  3-phenyl-4-methyl-5-pyrrolidinoethoxy pyrazole.

  As in Example 1, 8 g of 3-phenyl-5-pyrazolone are placed in 60 ml of dioxane and heated under reflux in a nitrogen atmosphere, then 3.9 g of potassium carbonate are added. The reaction mixture is refluxed for about 1 hour, and 13 g of N- (2-chloro) are added gradually.

ethyl) pyrrolidine.

  After 4 hours of reaction while maintaining the mixture under reflux, the

  solvent by evaporation in vacuo, and extraction is carried out.

  After recrystallization from cyclohexane, 3.5 g of phenyl-3 are obtained.

  4-methylpyrrolidinomethoxy-5-pyrazole (26% yield).

  Melting point: F = 88 ° C (cyclohexane) Thin layer chromatography (TLC): Rf = 0.4 (ethyl acetate + 10% diethylamine) The corresponding maleate, obtained by the usual techniques, has a

  mp = 158-159 ° C (ethanol).

EXAMPLE 3

  p-Chlorophenyl-3-piperidinopropoxy-5-pyrazole.

  In a 500 ml flask equipped with a refrigerant with chloride guard

  Calcium, a dropping funnel, a thermometer and an azo-

  19.4 g of p-chlorophenyl-3-pyrazolone are placed in 60 ml of dimethyl

  formamide anhydrous formamide, then the solution is degassed by bubbling a stream of nitrogen cooled to about 5 C and 2.8 g of hydride

  Sodium The temperature of the mixture is allowed to rise to

  ambient temperature, then gradually heated to 40 C, is added dropwise 17.4 g of 3-chloropropylpiperidine and allowed to react for

about 1 Oh.

  After evaporation of the solvent under vacuum, acid-base extraction, and recrystallization from isopropanol, 10.7 g of p-chlorophenyl-3-piperidinopropoxy pyrazole (yield 30%) are obtained.

  during the purification, approximately 25% of the p-chlorophenyl-3 pyrazolo

  n-5 starting material and about 3 g of p-chlorophenyl-3 piperidinopropyl2

  pyrazolone as a byproduct.

  Melting point: mp = 1400 ° C (isopropanol) IR (Nujol): v = 3250, 1510 cm -1 NMR spectrum (CDCl3): = 1.6 (6H), 2.1 (2H), 2.6 (6H), 4.3 (t, 2H),

6.2 (s, 1H), 7.8 (q, 4H) ppm.

EXAMPLE 4

  3-phenyl-4-methyl-5-morpholinoethoxy pyrazole.

  The procedure is as in Example 1, by placing 8 g of 3-phenyl-5-pyrazolone in 60 ml of dioxane. The mixture is refluxed and 4.1 g of carbonate are added.

  of potassium, then progressively 7.8 g of N- (2-chloroethyl)

  pholine. When the reaction is complete, after extraction and recrystallization from isopropanol, 5.1 g of 3-phenyl-4-methyl-5-morpholinoethoxy pyrazole are obtained (36% yield). Melting point: F = 100 ° C (isopropanol) TLC: Rf = 0 , 60 (ethyl acetate + 10% diethylamine) The corresponding maleate, prepared by the usual technique, by the action of maleic acid in ethanol, has a melting point F = 1560 C.

EXAMPLE 5

  3-phenyl-5-morpholinoethoxy pyrazole.

  In a 250 ml flask equipped with an azeotropic distillation apparatus and a dropping funnel, 9.6 g of ethyl benzoylacetate are dissolved and

  19.7 g of N- (2-hydroxyethyl) morpholine in 10 ml of toluene.

  The toluene ethanol azeotrope is distilled off and pure toluene is added at the same time. The reaction is substantially complete in about 4 hours. The toluene is washed with distilled water and then with water saturated with sodium chloride. calcium, and dried over sodium sulphate and

  evaporated to dryness 12.4 g of morpholino benzoylacetate are thus obtained.

  ethyl (yield 90%) as a yellow oil.

  0.2 g of hydrated hydrazine, 15 ml of ethanol, are placed in a flask of 0.1 ml.

  absolute and 1.6 ml of concentrated hydrochloric acid is heated to reflux and 1.4 g of morpholinoethyl benzoylacetate obtained as

  above is maintained at reflux for about 2 hours, and the reaction

  The ethanol is then evacuated in vacuo, and then it is drowned with water and extracted with chloroform to isolate approximately 0.1 g of 5-ethoxy-3-phenylpyrazole. The aqueous phase is alkalinized.

  then extracted with chloroform to give 0.5 g of 3-phenyl-morpholine

  5-ethoxy pyrazole (36% yield) Melting point: F = 100 C (isopropanol) -1 IR spectrum (Nujol) v = 3260, 1595, 1510 cm

EXAMPLES 6 to 23

  By proceeding as indicated in Example 1, but appropriately modifying the starting pyrazolone and haloalkylamine, the products listed in the table below, as well as their salts, the

  characteristics (melting point, recrystallization solvent and chroma-

  thin layer film with an eluent of 10% ethyl acetate and 10% diethylamine) are also mentioned at the same time.

board.

(see table on pages 10 and 11)

  Experiments carried out on aryl-3-alkoxy-5-pyrazoles

  forms of the invention have revealed interesting pharmacological and toxicological properties justifying their application

  possible in veterinary and human therapeutics.

Toxicological properties

  Acute toxicity of the derivatives of the invention has been studied by administrators.

  oral administration (PO) to the mouse (10 animals, 5 males and 5 females per dose) and calculation of the 50 lethal dose (LD 50) according to the method of Litchfield and Wilcoxon (J Pharmacol 1949, 96, 99-113). table 1

  presents the LD 50 values of the derivatives according to the invention.

  In some cases, LD 50 has also been studied after intravenous

peritoneal (I P) derivatives.

EXAMPLES 6 to 23

Ex Ar 6 _ & / ci 7 -0 -c

8 -0

9 -0

_ Cl il G /

12 O

13 -0

14 -0

R H H H H H CH 3 H H CH 3

NR 1 R 2

-ND -Ni

-N (CH 3) 2

-ND -N, o -ND -Ni -ND CD n FOC

2,117

2,128

3 (oil)

2 70-72

2 'L 20

2 80

  2 (oil) 3 (oil) 3 (oil) Rf * 0.65 OY 60 0.45 0.55 MO 0.3 0.35 0.55 OP 5 Salt tartrate maleate maleate maleate maleate ma 16 ate maleate oxalate maleate FOC

116-117

  k_Co r o ui LQ% O% O 01% _c 16 G-17 & C 18 G-19 19 _G_ here 21 -0 -c

22 - O

23 -Cl _GCl * C.C M: Acetate

-N (CH 3) 2

r_ \

-N O

\ -J

-N (CH 3) 2

  -N, -ND -ND-, -N, O -ND (oil) (oil) CH 3 CH 3 CH 3 CH 3 CH 3 H CH 3

-CH 2-C 6 H 5

  H O., 3 Op 5 Ot 45 0.70 Oe 6 ot 5 o Op 55 0.45 0.44 maleate hydrochloride tartrate maleate tartrate -158

102-118

  F_ I-, maleate tartrate tartrate maleate

152-153

  of ethyl + 10% diethylamine, and the like.

TABLE 1

LD 50 P 0.

  mg / kg 1,000 oo 1,000 1,000 1,000 400 b 800 1,000

250 to 500

500 to 1,000

at 250

500 to 1,000

500 to 1,000

500 to 1,000

750-

DL 50 I P.

mg / kg

250 to 500

at 250

250 to 500

62 to 125

  1. Cardiovascular Tolerance Cardiovascular tolerance has been studied in isolated atria of

  guinea pig, on the anesthetized rat and on the anesthetized dog.

  On the isolated guinea pig atrium, the preparation makes it possible to measure the contractile force of the guinea pig atrial myocardium and the frequency of the atrial contractions. At the concentration of 1 μg / ml of the bath solution, the tested derivatives cause a decrease in the contraction frequency of 15 to 75% (average -43.25%) compared to the pre-treatment controlled period At the same concentration, the contraction force varies from 0 to -80% compared to the control period (variation average

-37.5%).

EXAMPLE

  Properties In the anesthetized rat, the derivatives according to the invention, administered at doses of 6 to 25 mg / kg, cause a decrease in heart rate (5 to 40%), aortic flow, and systolic blood pressure. (4 to, o). In the anesthetized dog, the results obtained with regard to hemodynamic tolerance are summarized in table 2 below, which indicates the percentages of variation of hemodynamic parameters with respect to

  the pre-treatment control period for the derivatives of Examples 2 and 4.

  The parameters were recorded using: Catheters connected to pressure sensors (blood pressure, left ventricular pressure and its first derivative dp / dt); electromagnetic flow meter on the aorta (aortic flow); electrocardiograph; strain gauge placed on the left ventricular myocardium (force

myocardial contraction).

  The derivatives are injected intravenously, a dose every 30 minutes or so and their effects are measured 20 minutes after the end of

  injection (duration of injection 2 minutes).

TABLE 2

  Hemodynamic effects in the anesthetized dog (the effects are expressed as a percentage of variation from the pretreatment control period)

EXAMPLE 4

D O S E S

1 + 3 + 1

  Systolic blood pressure Heart rate Heart rate Systolic volume Strength myocardial contraction (dp / dt) l / p (mg / kg)

LO + 20 + 40

0 O O

0 0 18

0 23 34 11

0 23

+ 5 + 10 + 26 + 42 + 52

21 10

M

+ 10 + 2

EXAMPLE 2 D O S E S (mg / kg)

0.5 + 1 + 3 + 5 + 10 + 10

  Blood pressure + 4 O 8 12 20 systolic Heart rate 0 8 8 8 8 8 Cardiac output O -5 5 20 37 45 Systolic volume 0 + 3 + 3 12 31 40 Contraction force OO 20 20 10 20 myocardium (dp / dt The results shown in Table 2, as well as the analogous results obtained with the other derivatives according to the present invention, show that the derivatives cause in the dog the following modifications: the systolic blood pressure does not change not (derived from Examples 4 and 9), or moderately decreased (derived from Examples 2, 14, and 19) Thus, for derivative No. 2, this decline only appears after the cumulative dose of 4.5 mg / kg ; the heart rate does not change (derived from Examples 4 and 19), or decreases moderately (derived from Examples 9, 2 and 14);

  the cardiac output decreases in all cases.

  It remains moderate since a drop of 20% O is reached only with cumulative doses greater than 4 mg / kg (derived from Examples 4, 9 and 19) or even greater than 9 mg / kg (derived from example 2); the strength of the ventricular myocardial contractions increases after the injections of the derivative n 4, does not vary significantly with

  derivatives 9 and 14, decreases with derivatives 2 and 19 There also -

  this decrease, when it exists, remains moderate (maximum of -20 G

  for n 2 derivative after injection of 4.5 mg / kg to 29 mg / kg).

  These results show that the cardiovascular tolerance in dogs is satisfactory since the effects are limited to a moderate drop in cardiac output while force of myocardial contractions, pressure

  Systolic blood pressure and heart rate vary differently.

2 Electrophysiological tests.

  The maximum frequency monitoring test studies the maximum frequency of stimulation that can result in the contraction of an isolated atrium.

  guinea pig placed in a solution containing a derivative according to the invention.

  The measurement is carried out before (control period), then after

  derivation of the derivative in the solution.

  Table 3 below shows the percentages of decrease of the maximum frequency followed, for a concentration of 10 mg / i of each of the derivatives

  The results obtained show that the derivatives

  forms to the invention increase the atrial refractory period of 12

at 56%.

TABLE 3

Examples

he

A 5% MFS

  In addition, the electrophysiological study was carried out in the ances-

  closed-chest pentobarbital thesis, using bipolar catheter-electrodes introduced into the cardiac cavities by transcutaneous venous and arterial pathways, to measure sinus automaticity, intracardiac conduction times, and refractory periods

  effective and functional heart.

  During the electrophysiological study, the derivatives are injected

  intravenous in 2 minutes for each dose and 30 minutes apart.

  The measurement of the different parameters is carried out before the injection of the first dose (control period) and 10 to 28 minutes after the injection of each dose of the substance It is noted that the sinus automaticity is not significantly depressed likewise the conduction velocity between the atria and the atrioventricular node On the other hand, the conduction slows down in the His-Purkinje system at a dose of 4.5 mg / kg and it is known that this parameter is very characteristic of the effects of

  Vaughan-Williams group I antiarrhythmic drugs (quinidine

  -like) The effective atrial and ventricular refractory periods

  The atrioventricular nodal functional refractoriness period elongates only moderately and the effects rapidly reach a plateau.

* maximum in the dose range studied.

3 Antiarrhythmic tests.

  The derivatives according to the invention are used in the aconitine test

  In this test, the anesthetized rat is intoxicated by a perfusion

  intravenous aconitine (aconitine nitrate solution: 15 mg / l, infusion rate: 0.4 ml / min) while the electrocardiogram is continuously recorded During the constant-rate infusion, the time to the appearance of ventricular arrhythmias,

  successively ventricular extrasystoles (VES), ventricular tachycardia

  (TV) and Ventricular Fibrillation (VF) -

  Animals are divided into control (untreated) and treated lots

  (different doses) The results are expressed as a percentage of allon-

  delay in the occurrence of arrhythmias in batches treated with.

  compared to the control group This prolongation of the delay of appearance of the arrhythmias corresponds therefore to a myocardial protection against the arrhythmic effects

aconitine.

  Table 4 below summarizes the results obtained with various derivatives

  according to the present invention.

TABLE 4

Injection dose mq / kg

DYSRHYTHMIAS

  ESV + 32 + 6 + 7 + 13 + 11 o O + 10 + 2 + 15

VENTRICULAR (%)

TV FV

+ 30 + 44

+ 28 + 46

+ 22 + 18

+ 21 + 18

+ 45 + 32

+ 28 + 38

+ 11 + 18

+ 6 0

+ 15 + 35

  The cardiac antifibrillation activity of the derivatives according to the invention was verified on the mouse by means of the Lawson's test, according to the method described by J W Lawson, J. Pharmacol Exp Therp 1968, 160 th

  22-31 and Cr Narcisse et al., Ann Pharm En 1979, 37, 325-330.

  Mice (20 per dose) receive an intraperitoneal injection of the

  10 minutes before being placed in a saturated chloroform atmosphere.

  As soon as the respiratory arrest is obtained, the thorax is open (5 to 10 s) and

  Check the condition of the heart: presence or absence of ventricular fibrillation.

  The effective dose (ED 50) of the studied derivative is the dose which protects the

  half of the mice against anoxic ventricular fibrillation.

  The results in Table 5 below show that the following derivatives

  the invention possess a good antifibrillatory activity.

Example

TABLE 5

Derivative DE 50 (mg / kq)

3 35

4 46

79

7 66

9 44

11 42.5

14 62

19 21.5

  In addition, the Harris test carried out on the dog according to the

  described in Circulation 1950, 1, 1318, shows that the following derivatives

  the invention leads to a decrease in ventricular extrasystoles.

  By way of example, the number of ventricular extrasystoles per minute decreases by about 50% during the 2 hours following the injection of the product, in the case of the derivative described in Example 10.

  antiarrhythmic (myocardial protection) increases with the injected dose.

  Finally, it can be seen that the derivatives according to the present invention have a local anesthetic power verified on the rabbit cornea (local contact anesthesia) after instillation of an eye drop containing the test derivative. For example, the derivatives described in Examples 2, 3, 4, 6, 7, and 9 are local anesthetics (100% anesthesia) in solution at

0.25% or 1%.

  These results show that the aryl-3-alkoxy-5-pyrazole derivatives according to the present invention possess interesting antiarrhythmic properties, as well as electrophysiological and good properties.

  hemodynamic tolerance, making it possible to envisage their application in tea-

  human and veterinary therapeutics, particularly in the treatment of

  various forms of cardiac arrhythmias.

  The derivatives according to the invention and their pharmaceutically acceptable salts can be administered in the usual forms, the principle

  active ingredient being diluted in a pharmaceutically acceptable carrier

  chosen, for example in the form of a tablet, capsule, dragee,

  sitoire, injectable solution or syrup.

  By way of example, the tablets may be prepared by mixing the derivative according to the invention or a salt thereof, with one or more

  solid diluents such as lactose, mannitol, starch, polyvinyl

  pyrrolidone, magnesium stearate, talc, etc. If appropriate, the tablets may comprise several layers superimposed around a core, according to the usual techniques, to ensure a progressive release or a delayed effect of the active ingredient The coating can by for example, consist of one or more layers of polyvinyl acetate,

  carboxymethylcellulose or cellulose acetophthalate.

  The derivative according to the invention may also be administered in the form of a syrup or an oral solution obtained by dissolving it, if appropriate.

  as a pharmaceutically acceptable salt, in water or glycerol

  cerol, for example, and adding, if necessary, a customary additive such as

sweetener and an antioxidant.

  Injectable solutions can be prepared according to the well-known techniques and are constituted for example by a solute containing a

  derivative according to the invention or a pharmaceutically acceptable salt thereof

  tables, dissolved in bidistilled water, a hydroalcoholic solution, propylene glycol, etc., or a mixture of these solvents Where appropriate,

  a suitable additive such as a preservative can be added.

  The dosage may vary according to the nature of the condition being treated, and the subject concerned. The doses administered daily are generally comparable to those of quinidine treatments, but may be

  adjusted by the practitioner according to the circumstances.

Claims (9)

R E V E N D I C A T IO N S   1-Aryl-3-alkoxy-5-pyrazoles, characterized in that they are represented by the general formula (I) R Ar - (CH 2) -N (I) NH wherein Ar represents an aryl group, substituted where appropriate; R represents a hydrogen atom or an alkyl, phenyl or benzyl group; R 1 and R 2, which may be identical or different, represent a hydrogen atom or an alkyl group, or together form a 5- to 7-membered heterocycle with the nitrogen atom to which they are attached; N is an integer of 1 to 4; as well as their acid salts.   2-Aryl-3-alkoxy-5-pyrazoles according to claim 1, characterized in that Ar is a phenyl group, or a phenyl group substituted by one or more halogen atoms or alkyl, alkoxy, cyano, nitro or hydroxy groups. 3-Aryl-5-alkoxy-pyrazoles according to claim 2, characterized in that Ar is a phenyl group, or a phenyl group substituted with one or several atoms of chlorine.   4-Aryl-3-alkoxy-5-pyrazoles according to claim 1, characterized in that R is a hydrogen atom, a lower alkyl group of 1 to 4 atoms carbon, or a benzyl group.   Aryl-3-alkoxy-5-pyrazoles according to claim 1, characterized in that R and R 2 represent a lower alkyl group of 1 to 4 carbon atoms, or form, with the nitrogen atom to which they are attached, a heterocycle of 5 to 7 links including, where appropriate, one or more   other heteroatoms selected from nitrogen and oxygen.   6-Aryl-3-alkoxy-5-pyrazoles according to claim 5, characterized in that R 1 and R 2 form, with the nitrogen atom to which they are attached, a pyrrolyl, pyrrolidinyl, piperidyl, azepinyl or oxazolidinyl group,   pyrazolyl, piperazinyl, imidazolyl, morpholinyl, or pyrazolinyl.   Pharmaceutical composition characterized in that it contains a   aryl-3-alkoxy-5-pyrazole according to any one of the preceding claims.   dives, or a pharmaceutically acceptable salt thereof, diluted the case   in a suitable medium.   8 Process for the preparation of aryl-3-alkoxy-5-pyrazoles according to claim 1, characterized in that a pyrazolone of general formula (II) R Ar (II) is reacted N NN   In which Ar and R have the same meaning as in formula (I), in basic medium, with a haloalkylamine of general formula (III): X- (CH 2) n N R 1 R 2 (III) in which X is a halogen atom, and n, R 1 and R 2 retain the   definitions given in formula (I).   Process according to Claim 8, characterized in that the reaction is carried out in the presence of a base chosen from an alkali metal hydride, an amide, a carbonate or an alkoxide or an amine, in a solvent organic.   Method according to one of claims 8 and 9, characterized   in that the pyrazolone of formula (II) is dissolved in an organic solvent under a nitrogen atmosphere, a base is added, and then   haloalkylamine of formula (III).   11 Process for the preparation of aryl-3-alkoxy-5-pyrazoles according to claim   cation 1, characterized in that an alkyl aroylacetate of general formula (IV) is reacted: Ar-C-CHR-C-OC H   25 (IV)   Wherein Ar and R have the same meaning as in formula (I), with an aminoalcohol of general formula (V): HO- (CH 2) n -NR 1 R 2 (V) on, R 1 and R 2 have the same meaning as in formula (I), to obtain a compound of formula (VI): Ar-C-CHR-, - (CH 2) n -NR R (VI) O 2 on which cyclization is carried out at medium of hydrazine in an acid medium. Process according to Claim 11, characterized in that the reaction of the ethyl aroylacetate of formula (IV) and the aminoalcohol of formula   (V), is carried out in a solvent allowing azeotropic distillation.